Evidence derived from clinical observations indicates that small numbers of tumor cells can exist in a dormant state in clinically normal persons or can persist in patients receiving anti-tumor therapy who have attained clinical tumor remissions. Little is known of the host-tumor cell interactions that result in the establishment of this dormant tumor state. Subcutaneous implantation of DBA/2-derived L5178Y cells into DBA/2 mice followed 10 days later by nodule excision protected 100% of mice from the rapid outgrowth of an intraperitoneal challenge of L5178Y cells given 7 days post excision. Challenged mice remained clinically normal for 48 to 250 days before onset of an ultimately fatal tumor outgrowth. The numbers of L5178Y cells in the peritoneal cavity increased logarithmically for 4 days after challenge and then declined to low but detectable levels which persisted throughout the clinically normal period. Cells active in 18-hour in vitro cytolytic assays against 51Cr-labeled L5178Y target cells were found in the peritoneal cavity. The effector cells were determined to be Thy 1.2 positive. Their activity was tumor-specific and reached peak levels 4 days after tumor challenge and then gradually declined to undetectable levels during the following 70 days. Tumor emergence occurred most frequently during the period when CMC activity was no longer demonstrable in the remaining clinically normal mice. We propose to use this model system to (1) identify the host immune and non-immune components that act on tumor cells to establish and maintain the tumor-dormant state and (2) characterize the events that lead to breakdown of the tumor-dormant state and outgrowth of tumor. An understanding of the interactions involved in tumor dormancy should greatly facilitate the development of methods for prolonging the tumor-dormant period and ultimately the complete elimination of residual tumor cells.